DESCRIPTION (Applicant's Abstract): The broad objective of this research proposal is to elucidate at the molecular level the mechanism by which ATP modulates the signal transduction activities of the membrane guanylate cyclase (GC) family. This transduction mechanism is linked to the physiological processes of phototransduction, fluid secretion, and hypertension, and the emerging evidence suggests that it may also be linked to the neuro-sensory processes. Recent studies suggest that a common feature of all members of the GC family is their regulation by ATP. ATP is obligatory for the signal transduction activities of the two members of the natriuretic factor (NF) receptor GC family, atrial natriuretic factor receptor GC (ANF-RGC) and type C natriuretic factor receptor GC (CNP-RGC). ANF is a powerful physiological regulator of the processes of diuresis, water balance and blood pressure, and CNP appears to regulate the centrally-related processes of fluid secretion and blood pressure. The signal transduction mechanisms of ANP and CNP appear to be identical, occurring through their respective guanylate cyclases, ANF-RGC and CNP-RGC. ATP exhibits its activity by directly binding to a defined cyclase sequence motif, termed ARMs (stimulatory ATP regulator module), and a single amino acid residue acts as a bimodal switch in modulating both ligand binding and transduction activities of ANF-RGC and CNP-RGC. The ligand binding activity resides in the defined extracellular portion, the catalytic cyclase activity at the C-terminal end and the two cyclase activities are synchronized through ARMs. Thus, the NF signal transduction system is precisely threaded through its ordered multifunctional domains, termed modules: ligand binding, transmembrane, ARM and catalytic cyclase. Hence, this system has been termed a "multimodule signal transduction system". AIM 1 is to reveal the complete configurational identity of the ATP blinding pocket that defines functional ARMs. In keeping with the multiple signal transduction concept, ATP appears to have an additional activity of ANF-RGC, CNP-RGC and the phototransduction linked guanylate cyclase (ROS-GC). Identity of this inhibitory domain is unknown. Preliminary evidence indicates that this inhibitory effect is not mediated by ARMs, the kinase-like domain or the core-catalytic cyclase domain. This site exists in the C-terminal domain. To differentiate this potential ATP inhibitory module from that of the stimulatory ARM module, this module has been termed as ARMi. AIM 2 is to localize the ARMi in ANF-RGC, CNP-RGC and ROS-GC. Although the proposed research is most basic in nature, its ramifications are directly related to the molecular understanding of the pathology of vision, neurological disorders, heart disease, hypertension and fluid regulation.